PROJECT SUMMARY Obstructive sleep apnea (OSA) occurs in 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and the only clinical guideline for treating the disorder is continuous positive airway pressure (CPAP); that treatment helps ventilation, but does not resolve psychological comorbidities such high depressive symptoms. Since these comorbidities are regulated by the brain, a possible mechanism is impaired neural regulation due to injury from intermittent hypoxia in OSA. We found that people with OSA show brain injury brain in regions that regulate cognition and mood, including the hippocampus. Our earlier study showed female OSA patients have an even greater extent of injury and higher levels of symptoms than male OSA patients. Furthermore, while we found lower cognitive performance in untreated OSA patients, our pilot data showed CPAP resolving these deficits; this improvement in cognition was accompanied by a resolution of the hippocampal injury in a cognitive subregion of the hippocampus (CA1). However, CPAP did not improve depressive symptoms or hippocampal injury in depression-related subregions (posterior hippocampus CA2/3, tail). We therefore hypothesize that in OSA there is 1) a link between brain structure and psychological function, and 2) a positive impact of CPAP on cognitive function and structure, but not on depressive symptoms or depression-related structure. We will test these hypotheses in 60 newly-diagnosed OSA females and males matched for disease severity. We will assess the influence of six months of CPAP on symptoms and brain injury in the OSA patients. We will assess hippocampal injury based on precise regional volume measures from high- resolution MRI scans. Cognitive performance will be measured with the Montreal Cognitive Assessment (MoCA) tool, and depressive symptoms with the nine-item Patient Health Questionnaire (PHQ-9). We will assess separately in females and males 1) what hippocampal changes are reversible with CPAP, 2) whether MoCA and PHQ-9 scores are associated with injury in the CA1 and posterior hippocampus regions, and 3) whether changes in symptoms are associated with changes in injury. The findings will provide evidence whether cognitive and mood symptoms in OSA relate to brain injury in the hippocampus, and whether treatment resolves the brain or psychological deficits, and whether such deficits are worse in women with the disorder. We will control for age- related changes and 6-12 month CPAP effects in subsets of 30 control and OSA subjects. The findings will help explain sex-specific injury in OSA, and suggest interventions for symptoms. These findings may point to CPAP for reversible injury (e.g., inflammation), to therapies that will ?retrain? brain circuitry, or to neuroprotection approaches to prevent further injury (e.g., enhance cerebral blood flow, breathing exercises).